This invention relates to microspheres. More particularly it relates to processes for the preparation of microspheres of a polymer and a core material and to products produced thereby. In one particular aspect it relates to processes for the preparation of microspheres of a polymer and a drug and to products produced thereby.
Broadly, the microspheres of this invention may be described as: microcapsules of a core material, e.g., drug, and a polymer wherein the polymer coats a drug particle; or microprills which are homogeneous mixtures of a core material, e.g., drug, and a polymer. The processes of this invention are directed to the preparation of microspheres by novel phase separation techniques.
Microencapsulation by phase separation techniques is known in the prior art. For example, U.S. Pat. No. 3,242,051 describes a microencapsulation process for coating particles by phase separation in a nonaqueous medium.
Various prior art publications have reviewed microencapsulation by phase separation and these include:
"Microencapsulation" by Louis A. Luzzi in Journal of Pharmaceutical Sciences, Vol. 59, No. 10, 1367-1376 (1970); "Microencapsulation" by Wolfgang Sliwka in Angew. Chem. Internat. Edit., Vol. 14, No. 8, 539-550, (1975); "A Review of Microencapsulation" by Nawal N. Salib in Pharm. Ind., Vol. 39, No. 5, 506-512, (1977); "Microencapsulation, Processes and Applications," edited by Jan E. Vandegaer, Plenum Press, N.Y., 1974; "Microencapsulation," edited by J. R. Nixon, Marcel Dekker, Inc., 1976.
The techniques set forth in these publications have in common the fact that the core material of the desired particle size is dispersed in a continuous phase which is comprised the polymeric wall material in solution. The polymeric material is then deposited on the core material by gradual precipitation of the polymer. This is achieved either by the use of precipitants, by changes in temperature or by removal of the solvent by dilution or distillation.
One application of temperature was reported in U.S. Pat. No. 3,531,418 wherein a mixture of polymer and core material was heated to dissolve the polymer and then slowly cooled to room temperature to allow the polymer to separate and encapsulate the core material. Another example of the use of temperature was reported in U.S. Pat. No. 3,657,144 wherein a mixture of polymer and core material was heated in a volatile solvent for the polymer with an appreciably less volatile nonsolvent. Evaporation of the volatile solvent by heating caused the polymer to separate and coat the core material.
U.S. Pat. No. 3,773,919 broadly describes the microencapsulation of a drug with a biodegradable polymer (polylactide polymer) by a phase separation process (similar to that disclosed earlier in U.S. Pat. No. 3,242,051). The process consists of (1) suspending drug particles in a solvent system in which the polymer is soluble but the drug is not soluble; and (2) adding an agent incompatible with the polymer-solvent system, such as an incompatible polymer, a nonsolvent for the polymer, or a salt, or to vary the conditions such as temperature or pressure, to precipate the polymer thus coating the drug particles.
The prior art use of temperature for preparing microcapsules by phase separation had been limited to room temperature or higher. None of the prior art cited discloses the use of low temperature phase separation process.
Prior to U.S. Pat. No. 3,773,919 it was disclosed in U.S. Pat. No. 3,336,155 that it is often impossible to obtain discrete microencapsulated particles by a phase separation process and that it was necessary to incorporate a mineral silicate (e.g., talc) during the addition of a nonsolvent to minimize the deleterious adhesion and coalescense of the encapsulated particles. However, these products would be unacceptable in many applications, for example, in pharmaceutical injectable formulations.
U.S. Pat. No. 3,887,699 discloses the preparation of homogeneous mixtures of a polymer and a drug which are formed by mixing the drug and biodegradable polymer in a suitable solvent to form a homogeneous solution. The solvent is then removed and the residue is subsequently formed into the desired shape by molding, extruding, etc.
Thus there is no satisfactory procedure reported in the prior art for obtaining discrete, spherical microspheres of polymer and a core material by phase separation which would be suitable in a broad range of applications.